RESUMEN
This paper reports a generic method for constructing n-fold covers of 3D conservative chaotic systems, which is derived from the theory of the generalized Hamiltonian system. Three typical example systems are constructed based on the proposed method, and their different n-fold cover chaotic flows are investigated theoretically and numerically. For each example system, the motion trajectories are both conservative and chaotic, which can be verified by the Lyapunov exponents, and it is interesting to find that the emergence of n-fold cover conservative chaos mainly relays on the corresponding Hamiltonian. Numerical results show that the proposed generic method is effective to construct n-fold covers of 3D conservative chaotic systems, such as a 3-fold cover in the direction of the y-axis, 2×3-fold cover on the x-y plane, and 2×3×2-fold cover in the 3D phase space. This study also demonstrates that based on appropriate skew-symmetric nonconstant matrices, the n-fold cover conservative chaos can be obtained by changing the Hamiltonian.
RESUMEN
We present a high-repetition-rate, high-pulse-energy, high-beam-quality, and high-average-power laser system using an ultraclean closed-type stimulated-Brillouin-scattering phase-conjugate mirror (SBS-PCM). By controlling microparticles of SBS-PCM down to 40 nm, thermal load capacity of such closed-type SBS-PCM was greatly improved, which presented the best reported cleanliness. The closed-type SBS-PCM, lacking scanning wedge plates, achieved reflectivity as high as 92% and showed no optical breakdown phenomena or obvious thermal effects at a 500 Hz pulse-repetition frequency (PRF). Operation at 550 W output power, approximately 1.1 J pulse energy, and beam quality M2 of approximately 2 represents, to our knowledge, the best reported performance. Thermal phase distortion was compensated, and the maximum-output-power pulse-width compression improved from 30 ns to approximately 10 ns.
RESUMEN
In this Letter, we present an adaptive aberration correction system to simultaneously compensate for aberrations and reshaping the beams. A low-order aberration corrector is adapted. In this corrector, four lenses are mounted on a motorized rail, whose positions can be obtained using a ray tracing method based on the beam parameters detected by a wavefront sensor. After automatic correction, the PV value of the wavefront is reduced from 26.47 to 1.91 µm, and the beam quality ß is improved from 18.42 to 2.86 times that of the diffraction limit. After further correction with a deformable mirror, the PV value of the wavefront is less than 0.45 µm, and the beam quality is 1.64 times that of the diffraction limit. To the best of our knowledge, this is the highest performance from such a high-power, high-pulse repetition rate Nd:YAG solid-state laser ever built.
RESUMEN
Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 µM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Humanos , Ratones , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Relación Estructura-ActividadRESUMEN
Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of mammary carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Comparison of Trim24COE metaplastic carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24COE gene signature reveals strong correlation with human MpBC tumors and MpBC patient-derived xenograft (PDX) models. Global and single-cell tumor profiling reveal Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. Here, we find that pharmacological inhibition of these pathways in primary Trim24COE tumor cells and TRIM24-PROTAC treatment of MpBC TNBC PDX tumorspheres decreased cellular viability, suggesting potential in therapeutically targeting TRIM24 and its regulated pathways in TRIM24-expressing TNBC.
Asunto(s)
Carcinosarcoma/genética , Proteínas Portadoras/genética , Neoplasias Mamarias Experimentales/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Neoplasias de la Mama Triple Negativas/genética , Animales , Mama/patología , Carcinosarcoma/patología , Proteínas Portadoras/metabolismo , Ensayos Clínicos como Asunto , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Transgénicos , Proteínas Nucleares/metabolismo , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-met/genética , RNA-Seq , Análisis de la Célula Individual , Factores de Transcripción/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Secuenciación Completa del Genoma , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We have previously identified a subset of cancers harbouring homozygous deletion of the glycolytic enzyme enolase (ENO1) that have exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. Here, we show that a small-molecule enolase inhibitor, POMHEX, can selectively kill ENO1-deleted glioma cells at low-nanomolar concentrations and eradicate intracranial orthotopic ENO1-deleted tumours in mice at doses well-tolerated in non-human primates. Our data provide an in vivo proof of principle of the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential use across a range of therapeutic settings.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Proteínas de Unión al ADN/genética , Inhibidores Enzimáticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Fosfopiruvato Hidratasa/antagonistas & inhibidores , Proteínas Supresoras de Tumor/genética , Animales , Línea Celular Tumoral , Femenino , Glioma/tratamiento farmacológico , Glucólisis/efectos de los fármacos , Humanos , Macaca fascicularis , Masculino , Ratones , Ratones SCID , Fosfopiruvato Hidratasa/genética , Medicina de Precisión , Eliminación de Secuencia , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.
Asunto(s)
Inhibidores Enzimáticos/química , Glutaminasa/antagonistas & inhibidores , Triazoles/farmacocinética , Administración Oral , Animales , Línea Celular Tumoral , Perros , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Glutaminasa/genética , Glutaminasa/metabolismo , Semivida , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Microsomas/metabolismo , Unión Proteica , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Relación Estructura-Actividad , Triazoles/química , Triazoles/metabolismoRESUMEN
Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC. SIGNIFICANCE: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.
Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Experimentales/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Acrilamidas/farmacología , Compuestos de Anilina/farmacología , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Mutación , Neoplasias Experimentales/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Utilizing structure-based drug design, a 4-aminoimidazole heterocyclic core was synthesized as a replacement for a 2-aminothiazole due to potential metabolically mediated toxicity. The synthetic route utilized allowed for ready synthesis of 1-substituted-4-aminoimidazoles. SAR exploration resulted in the identification of a novel cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Quinasa 5 Dependiente de la Ciclina/metabolismo , Imidazoles/química , Proteínas del Tejido Nervioso/metabolismo , Animales , Sitios de Unión , Células CACO-2 , Cristalografía por Rayos X , Ciclina E/antagonistas & inhibidores , Ciclina E/metabolismo , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Diseño de Fármacos , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-ActividadRESUMEN
Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (30) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound 30 demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of N-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (Cav,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of 30 at or above targeted efficacious plasma levels for 24 h, which became part of the human clinical plan.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Animales , Disponibilidad Biológica , Encéfalo/fisiología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Imidazoles/química , Imidazoles/metabolismo , Imidazoles/farmacocinética , Imidazoles/farmacología , Concentración 50 Inhibidora , Memoria a Corto Plazo/efectos de los fármacos , Simulación del Acoplamiento Molecular , Conformación ProteicaRESUMEN
Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.
Asunto(s)
Neoplasias/patología , Fosforilación Oxidativa , Animales , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Metabolismo Energético , Glucólisis/efectos de los fármacos , Células HEK293 , Humanos , Ácido Láctico/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Mitocondrias/metabolismo , Nucleótidos/biosíntesis , Carga Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/metabolismo , Perros , Haplorrinos , Humanos , Ratones , Simulación del Acoplamiento Molecular , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/farmacocinética , RatasRESUMEN
Chronic liver disease is one of the most common diseases that threaten human health. Effective treatment is still lacking in western medicine. Semen Persicae (Taoren) and Flos Carthami (Honghua) are known to relieve acute hepatic injury and inflammation, improve microcirculation, and reduce tissue fiber. The aim of our study is to investigate the potential mechanisms of Taoren-Honghua Herb Pair (THHP) in murine model of chronic liver disease caused by Carbon Tetrachloride (CCl4). Mice were randomly divided into seven groups: (1) blank, (2) model, (3) control (colchicine, 0.1 mg/kg), (4) THHP (5.53, 2.67, and 1.33 g/kg), and (5) Tao Hong Siwu Decoction (THSWD) (8.50 g/kg). Histological change and microvessels density were examined by microscopy. Hepatic function, serum fibrosis related factors, and hepatic vascular endothelial growth factor (VEGF) were measured with ELISA. VEGF, kinase insert domain-containing receptor (KDR), Flt-1, and Akt mRNA expression in hepatic tissue were determined with PCR. Tissues of Akt, pAkt, KDR, and Flt-1 were measured with western blotting. Data from this study showed that THHP improved hepatic function and restrained the hepatic inflammation and fibrosis. Its role in inhibiting pathological angiogenesis and hepatic fibrogenesis may be through affecting the angiogenesis-associated VEGF and its upstream and downstream signaling pathways.
RESUMEN
Two synthetic routes to a series of structurally novel kinase inhibitors containing a cis-1,3-disubstituted cyclobutane are described. The first route utilized addition of 3-aminocyclobutanol to 1,4-dinitroimidazole 5 as the crucial step in preparing 1, whereas the second route employed a novel 1,4-addition of 4-nitroimidazole 18 to in situ generated cyclobutenone 17 as the key reaction. This allowed for a stereoselective and shorter synthesis that eliminated the use of potentially explosive 1,4-dinitroimidazole 5. [structure: see text]
Asunto(s)
Butanos/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Fosfotransferasas/antagonistas & inhibidores , Ciclización , Inhibidores Enzimáticos/farmacología , Estructura Molecular , Nitroimidazoles/química , EstereoisomerismoRESUMEN
Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥ 1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Azetidinas/química , Barrera Hematoencefálica/metabolismo , Pirazoles/química , Pirazoles/síntesis química , Pirimidinas/química , Pirimidinas/síntesis química , Pirimidinonas/química , 3',5'-AMP Cíclico Fosfodiesterasas/química , Administración Oral , Animales , Azetidinas/síntesis química , Azetidinas/farmacocinética , Cristalografía por Rayos X , GMP Cíclico/líquido cefalorraquídeo , Ciclopentanos/síntesis química , Ciclopentanos/química , Ciclopentanos/farmacocinética , Bases de Datos Factuales , Perros , Diseño de Fármacos , Humanos , Modelos Moleculares , Estructura Molecular , Pirazoles/farmacocinética , Pirimidinas/farmacocinética , Pirimidinonas/síntesis química , Pirimidinonas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.
Asunto(s)
Antipsicóticos/síntesis química , Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/metabolismo , Esquizofrenia/tratamiento farmacológico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Reacción de Prevención/efectos de los fármacos , Sitios de Unión , Barrera Hematoencefálica/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cristalografía por Rayos X , GMP Cíclico/metabolismo , Bases de Datos Factuales , Diseño de Fármacos , Humanos , Técnicas In Vitro , Ratones , Ratones Noqueados , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Permeabilidad , Inhibidores de Fosfodiesterasa/farmacocinética , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/genética , Conformación Proteica , Relación Estructura-ActividadRESUMEN
High-throughput screening with cyclin-dependent kinase 5 (cdk5)/p25 led to the discovery of N-(5-isopropyl-thiazol-2-yl)isobutyramide (1). This compound is an equipotent inhibitor of cdk5 and cyclin-dependent kinase 2 (cdk2)/cyclin E (IC(50)=ca. 320nM). Parallel and directed synthesis techniques were utilized to explore the SAR of this series. Up to 60-fold improvements in potency at cdk5 and 12-fold selectivity over cdk2 were achieved.